3-alkylene hemithioketals and 3-enol ethers of steroids



United States Patent 3,354,153 S-ALKYLENE HEMITHIOKETALS AND S-ENOLETHERS 0F STEROIDS George Karmas, Bound Brook, N.J., assignor to OrthoPharmaceutical Corporation, a corporation of New Jersey No Drawing.Filed Dec. 7, 1965, Ser. No. 512,200 9 Claims. (Cl. 260239.55)

ABSTRACT OF THE DISCLOSURE A and A -hemithioketals of steroidal4-en-3-ones are intermediates for the preparation of the corresponding A-enol ethers through the cleavage of the sulfur to carbon linkage of thehemithioketal moiety.

as follows:

H+ HOCHzOHzSH wherein R is hydrogen, methyl, chloro or fluoro. The abovedescribed reaction is carried out according to a procedure such as thatof Djerassi and Gorman, I. Am. Chem. Soc., 75, 3703-8 (1953).

It has been found that the sulfur to carbon linkage of the hemithioketalmoiety is cleaved by treatment of the novel hemithioketals of thepresent invention with acetic anhydride in the presence of an acidcatalyst such as p-toluenesulfonic acid, to form the corresponding A-enol ethers. Typical reaction diagrams showing the cleavage of thehemithioketal are as follows:

H+ (CHSOO) 20 wherein R is hydrogen, methyl, chloro or fluoro.

3,354,153 Patented Nov. 21, 1967 ICC . O3; (OH CO) 2O 0 S CH3 C-SCHaCHzOThe novel A and A -hemithioketals and A thioenol ethers of the presentinvention exhibit important pharmacological properties as antilitteringagents. While the precise mode and site of action of all of the novelcompounds of the invention is not clearly understood, it has been foundthat compounds of the present invention exhibit progestational activity.

The novel hemithioketals of the invention are of the following formulae:

wherein R is hydrogen, methyl, chloro or fluoro, R is hydrogen ormethyl, R" is hydroxy, acetyl or acetoxy, R is hydrogen, lower alkyl offrom 1 to 8 carbon atoms, lower acyloXy of from 1 to 8 carbon atoms or-CECX wherein X is hydrogen, chloro or lower alkyl of from 1 to 8 carbonatoms and n is the integer 2 or 3.

5 The novel thioenol ethers of the following formula:

invention are of the wherein R is hydrogen, methyl, chloro or fiuoro, Ris hydrogen or methyl, R" is acetyl or acetoxy, R is hydrogen, loweralkyl of from 1 to 8 carbon atoms, lower acyloxy of from 1 to 8 carbonatoms or -CECX wherein X is hydrogen, chloro or lower alkyl of from 1 to8 carbon atoms and n is the integer 2 or 3.

Typical steroidal 4-en-3-ones from which the hemithioketals of thepresent invention may be prepared are:

' 6u-methyl-17a-acetoxyprogesterone 6a-methyl-17m-propionoxyprogesterone6a-fiuoro-17a-hydroxyprogesterone 6a-fluoro-17a-acetoxyprogesteronefiat-fluoro-17a-propionoxyprogesterone 6u-chloro-17a-hydroxyprogesterone6a-ch1oro-17a-acetoxyprogresterone a-chloro-17a-propionoxyprogesteronefiat-methyl-17a-hydroxy-19-norprogesterone 6a-methyl- 17 a-acetoxy-19-norprogesterone 6a-fiuoro-17a-hydroxy-19-norprogesterone6a-fiuoro-17a-acetoxy-19-norprogesterone l7a-methy1progesterone17a-hydroxyprogesterone 17a-acetoxyprogesterone17a-propionoxyprogesterone 17a-caproxyprogesterone17a-ethynyl-19-nortestosterone acetate6a-rnethy1-17a-ethyny1-19-nortestosterone acetate17a-(prop-1-yne-1-y1)-19-nortestosterone acetate The, following examplesillustrate the invention:

Example I .-.1 7u-acetoxypregn-5-ene-i20-dione- 3-ethylenehem'ithioketalA mixture. of 10.0 g. of 17u-acetoxyprogesterone,

ml.j of fl-mercaptoethanol, 500 mg. of p-toluenesulfom'c 7 acid and 500m1. of benzene is boiled under reflux for three hours, with constantseparation of water from the condensate by means of a Dean-Stark trap.After cooling to room temperature, the benzene solution is washed with asaturated aqueous sodium bicarbonate solution and then it is dried withanhydrous magnesium sulfate, filtered and evaporated to dryness undervacuum to obtain a mixture of crystalline solids. To this is added 300ml. of acetone and the resulting suspension is stirred and boiled gentlyfor five minutes. It is then cooled to 20 C. and filtered to removeinsoluble material. The filtrate of acetone-soluble material is boileddown to a volume of 40 ml. and this is cooled to 20 C., and againfiltered to remove more insoluble solid. The filtrate is now boiled downto 13 ml. and chilled to 0 C. to afford 1.0 g. of17a-acetoxypregn-5-ene-3,20-dione 3-ethylenehemithioketal, White flakeswhich melt at 218220 C. A second crop, amounting to 0.1-0.2 g. may beobtained by reworking of the mother liquor from the 1.0 g. portion.

A-nalysis.--Calcd. for C l-1 0 5: C, 69.43; H, 8.39. Found: C, 69.67; H,8.64.

06 -42 (chL).

Following the procedure of Example I, but starting with:

testosterone,

testosterone acetate, 17a-methyltestosterone, 17a-ethyltestosterone,17a-ethynyltestosterone, 17a-(hex-1-yne-1-yl)-testosterone,17u-chloroethynyltestosterone, 17a-methylprogesterone,17kx-hydroxyprogesterone, and 171x-propionoxyprogesterone there areprepared respectively,

5-androsten-17B-ol-3-one 3-ethylenehemithioketal,

5-androsten-l7/3-ol-3-one 17-acetate 3-ethylenehemithioketal,

17'a-methyl-5-androsten-17B-ol-3-one 3-ethylenehemithioketal,

17u-ethyl-5-androsten-17fi-ol-3-one 3-ethylenehemithioketal,

17a-ethynyl-5-androsten-17,8-01-3-one 3-ethylenehemithioketal,

17a-(hex-1-yne-1-yl)-5-androsten-17B-ol-3-one 3-ethylenehemithioketal,

17a-(chloroethynyl)-5-androsten-17B-ol-3-one 3-ethylenehemithioketal,

17kx-methylpregn-5 ene-3,20-dione 3-ethylenehemithioketal,

17u-hydroxypregn 5-ene-3,20 dione 3'-ethylenehemithi0- ketal, and

17u-propionoxypregn-5 ene3,ZO-dione 3'-ethylenehemithioketal.

Example II.3.- fl-acetylthioethoxy -1 7 aracetoxypregn'a-3,5-dien-20-0ne A mixture of 1.1 g. of 17a-acetoxypregna-5-ene-3,20-

dione 3-ethylenehemithioketal (as obtained in-Example- I), 1.0 g. ofp-toluenesulfonic acid monohydrate, and 20 ml. of acetic anhydride isstirred vigorously at 25 C. for fifteen minutes and then it is cooled to10 C. and 4 ml. of pyridine is added. This mixture is poured into 500ml. of an ice and water mixture to which 60 ml. of pyridine haspreviously been added. After the precipitated oil has become partiallycrystalline, it is separated by filtration and then dissolved in ml. ofethyl ether. The ether solution is dried with anhydrous potassiumcarbonate, and after filtration to remove drying agent it isreduced to avolume of 8 ml. Storing of this concentrated ether solution at 0 C.affords 0.48 g. of yellow prisimsof the desired enol ether. Later cropsof the same material, totalling 0.3 g., are obtained by furtherreworking of the motor liquor. The total of 0.78 g. of crude enol etheris now recrystallized from ethyl ether to afford 0.55 g. of3-(p-acetylthioethoxy)-17uacetoxypregna-3,5-dien-20-one, large yellowprisms which melt at 145-150 C.

Analysis.Calcd. fOl' C37H3305SI C, H, 8.08. Found: C, 68.45; H, 8.14.

[@ 103 (chL).

Following the procedure of Example II, but starting with:

there are prepared respectively,

3- (fi-acetylthioethoxy- 1 7,8-acetoxyandrosta-3,S-diene,

3- (fi-acetylthioethoxy -"17fi-acetoxyandrosta-3,5-diene,

3- (fl-acetylthioethoxy) 17a-rnethyl-17p-acetoxyandrosta-3 ,5 -diene,

3-(18-acetylthioethoxy) -17a-ethy1-17fl-acetoxyv androsta-3,5-diene,

3-(B-acetylthioethoxy) -17a-ethyny1-17fi-acetoxyandrosta-3 ,5 -diene,

3-(fl-acetylthioethoxy) 17a-(hex-1-yne-1-yl) 17 3- acetoxyandrosta-3 ,5-diene,

3 -(fl-acety1thioeth0xy) -*17a-chloroethynyl-17fiacetoxyandrosta-3 ,5-diene,

3-( fi-acetylthioethoxy) l 7oc-methylpregna-3,S-diene- 20-one, 1

3- (fi-acetylthioethoxy) -17ot-acetoxypregna-3,5-diene- 20-one, and

3-(,8-acetylthioethoxy) -17a-propionoxypregna-3,5-

diene-20-one.

Example III.6-methyl-17a-acetoxypregn-5-ene-3,20-

dione 3-ethylenehemithioketal A mixture of 2.5 g. of p-toluenesulfonicacid monohydrate and 1500 ml. of benzene is boiled under reflux for onehour, with separation of Water from the condensate bymeans of aDean-Stark trap. 50.0 g. of 6a-methyl- 17a-acetoxyprogesterone and 50ml. of fi-mercaptoetha- 1101 are added and this mixture is boiled underreflux for three hours with separation of water by means of theDean-Stark trap. After cooling to room temperature, the benzene solutionis washed with aqueous sodium bicarbonate, dried with anhydrousmagnesium sulfate, filtered and evaporated under vacuum to a viscousresidue of crude hemithioketal. The latter is dissolved in 100 ml. ofwarm acetone and this solution is chilled at to afford 17.0 g. of whiteprisms. Concentration and chilling of the mother liquor affords anadditional 3.0 g. as a second crop. Recrystallization of this total of20 g. from ethyl acetate finally affords 14.0 g. (in four crops) of6-methyl- 17oz acetoxypregn--ene-3,ZO-dione 3-ethylenehemithioketal,white flakes which melt at 223-227" C.

8 Analysis.Calcd. for (12 1 1330481 C, 70.00, H, 8.57- Found: C, 70.21;H, 8.47.

M 5.76, 5.81, 7.97, 9.15, 9.28, 10.30, 11.92,. -44.-0 (chl.) Followingthe procedure of Example III, but starting with:

6a-methyltestosterone, 6fi-methyl-testosterone, 6u-fluorotestosterone,6B-fiuorotestosterone, 6a-fluoro-17a-methyltestosterone,

60c, 17a-dimethyltestosterone, 6a-methyl-17a-ethynyltestosterone,6fi-me'thyl 17a-ethynyltestosterone, 6a-methyl17a-(prop-l-yne-yl)testosterone, 6a-methyl-'17a-ethyltestosterone,6ot-methyl-l7a-hydroxyprogesterone, Got-fluoro-17a-acetoxyprogesterone,6a-chloro- 17a-acetoxyprogesterone, 6ot-fluoro-l7a-hydroxyprogesterone,and 6-chloro-17u-hydroxyprogesterone there are prepared respectively,

G-methyl-S-androsten-17B-0l-3-0ne 3-ethylenehemithioketal,

6-fluoro-5-androsten-17,8-ol-3-one 3-ethy1enehemithioketal,

6-fluoro-17u-methyl-5-androsten=17fl-o1-3-one 3-ethylenehemithioketal,

6,17a-dimethyl-5-androsten 17fl-ol-3-one 3-ethylenehemithioketal,

6-methyl-17a-ethynyl-5-androsten-17B-ol-3-one 3-ethylenehemi-thioketal,

6-methy1-1 7a- (prop-'1 -yne-1-y1) -5-androsten- 17 3- ol-3-one3-ethylenehemithioketal,

6-methyl-17u-ethyl-5-androsten 17;8-ol-3-one 3-.ethylene-,

hemithioketal,

6-methyl-l7a-hydroXypregn-5-ene-3,20-dione 3-ethylenehemithioketal,

6-fluoro-17a-acetoxypregn-5-ene-3,20-dione 3-ethylenehemithioketal,

6-fluoro-17a-hydroxypregn-5-ene-3,20-dione S-ethylenehemithioketal, and

'fi-chloro-l7a-hydroxypregn-5-ene-3,20-dione 3-ethylenehemit-hioketal.

Example I V.3- B-acet? lthioethoxy -6-methyl-1 7 0L-acet0xypregna-3,5-dien-20-0ne To a solution of 10.0 g. ofp-toluenes'ulfonic acid monohydrate in 200 ml. of acetic anhydride isadded 10.0 g. of finely-divided 6 methyl 17a-acetoxypregn-5-ene-3,20-dione 3-ethylenehemithioketal (as obtained in Example III), and themixture is stirred at 25 C. for twenty minutes. The resulting clear redsolution is cooled to 10 C. and to it is added 50 ml. pyridine and thismixture is then poured into 2000 ml. of an ice and water mixture towhich 600 ml. of pyridine has previously been added. After theprecipitated oil has become partially crystalline, it is separated byfiltration and then dissolved in 200 ml. of ether. The ether solution iswashed with aqueous sodium bicarbonate solution and with Water, and thenit is dried with anhydrous potassium carbonate. After filtration toremove drying agent, the ether solution is reduced to a volume of 20 ml.and stored at 0 C. to effect crystalli zation of 3.3 g. of the enolether. The material remaining in the ethereal mother liquor is developedonto a chromatographic column of acidic alumina and eluted withether-plus-benzene (1:1) to afford 1.5 g. more of crude enol ether. Thecombined portions of enol ether are recrystallized from ethyl ether toafford 4.1 g. of 3-(13- acetylthioethoxy) 6-methyl-17a-acetoxypregna-3,S-dien- 1 .0-one as pale yellow prisms which melt at122124 C.

Analysis.Calcd. for C H O S: C, 68.93; H, 8.26. Foundt'C, 68.68; H,8.23.

[x1 --130(chl.).

Following the procedure of Example IV, but starting with:

there are prepared-respectively,

3 fl-acetylthioethoxy -6-methyl- 17 B-acetoxyandrosta- 3 ,S-diene,

3- B-acetylthioethoxy) -6-fiuoro- 17 fi-acetoxyandrosta- 3,5-di'ene,

3- B-acetylthioethoxy -6-fluoro- 17 u-methyl-17 ,3-

acetoxyandrosta-3,S -diene,

3- B-acetylthioethoxy -6, l7oc-dlIIl6thYl- 1718-acetoxyandrosta-3,S-diene,

3-(fi-acetylthioethoxy) -6-methyl-17a-ethynyl-17;8-

acetoxyand-rosta-3 ,5 -diene,

3- (e-acetylthioethoxy) -6-methyl-17a- (propl-yne- 1-yl) -17)8-acetoxy'androsta-3,5 -di'ene,

3 fi-acetylthioethoxy) -6-methyl- 17a-ethyl- 17,8.

acetoxyandrosta-3,5-diene,

3- (fi-acetylthioethoxy) -6-methyl-l7a-acetoxypregna- 3,5 -diene-20-one,

3 (B-acetylthioethoxy -6-fluoro-17a-acetoxypregna- 3,5 -diene-20-one,

S-(B-acetylthioethoxy)-6-chloro1l7a-acetoxypregna- 3,5-diene-20-one,

3- flaacetylthioethoxy -6-fluoro-l7a-acetoxypregna- 3,5 -diene- 20-one,andv 3 (e-acetylthioethoxy') -6-chloro,-. 1 7a-acetoxypregna- 3,5'-diene 20eone.

Example V.-17zx ethynyl 17 8 acetoxyestr 5 (10)- en 3 one 3ethylenehemithioketal (A) and 17aethynyl 17B acetoxyestr 5 en 3 one 3ethylenehemithioketal (B) A. A mixture of 60.0 g. of 17oz ethynyl 19nortestosterone, 60 ml. of-B mercaptoethanol, and 3.0 g. of ptoluenesulfonic acid monohydrate in 3000 ml. of benzene: is boiled.under reflux for three and one-half hours, .withlconstant' separation ofwater from the condensate by means of a Dean-Stark trap; After coolingto room-temperature, the benzene solution is washed with aqueous .sodiumbicarbonate solution and withv water, and then it is dried"with-anhydrous magnesium sulfate,

filtered to remove drying agent, andevaporated under vacuum to a viscoussemicrystalline residue. The latter is developed onto a chromatographiccolumn of neutral alumina. Elution with benzene, followed by ethylether, affords 25 g. of a mixture of products which must subsequently beseparated by crystallization techniques.

The 25 g. of hemithioketal mixture is boiled under refluxfor two andone-half hours with 800 ml. of acetic anhydride containing 2 ml. ofpyridine and then this solution-is cooled to 25 C. and poured into 4000ml. of ice and water mixture containing 30 ml. .of pyridine. The oilremainingv after the acetic anhydride has hydrolyzed becomes crystallineon storage of the hydrolysis mixture at 0 for twenty hours. The tackysolid is isolated by filtration and is dried in air, and'then it isboiled in 360 m1. of methanol. After filtration to clarify, themethanolic filtrate is allowed to cool slowly and is maintained at roomtemperature for two hours. The solid which has crystallized from themethanol is filtered off and dried to afiord 5.5 g. of crude Ahemithioketal, which is identified by its infrared absorption (seebelow). This is recrystallized twice from ethyl acetate to afford 3.6 g.of 17a ethynyl 17,5 acetoxyestr 5(10) en 3 one 3- ethylenehemithioketal(A), white prisms which melt at 178180 C.

Analysis.-Calcd. for C H O S: C, 72.00; H, 8.05.

Found: C, 72.01; H, 8.24.

[041 +37.2 (chl.).

B. On standing at 25 C. for four days, the methanolic mother liquor fromisolation of the A isomer (A, above) deposits a further quantity ofcrystalline material which is isolated by filtration to afiord 4.6 g. ofcrude A isomer, identified by its infrared absorption (see below).Further purification of this isomer is effected throughrecrystallization of its corresponding 17p 01 form, rather than theacetate which has been isolated.

The 4.6 g. of crude A isomer is boiled under reflux for twenty minuteswith ml. of methanol containing 1.2 g. of potassium hydroxide. Thissaponification mix ture is diluted with 800 ml. of water containing 2ml. of acetic acid and the 01 is extracted with three small portions ofmethylene chloride. The combined extracts are dried with anhydrousmagnesium sulfate, filtered, and then evaporated to a crystallineresidue which is recrystallized from ethyl acetate to ailord 2.7 g. of17a. ethynylestr 5 en 17/3 o1 3 one 3 ethylenehemithioketal, whitegranules which melt at 176-179".

Analysis.Calcd. for C H O S: C. 73.75; H, 8.44. Found: C, 73.58; H,8.68.

[@ +12.6 (chl.).

The purified A isomer (17 3 01) thus obtained is acetylated by boilingit under reflux for two hours in 55 ml. of acetic anhydride containingfour drops of pyridine. After cooling of the acetic anhydride solutionto 30 C., it is poured into 500 ml. of an ice and water mixture. Thecrystalline solid which forms after hydrolysis of the acetic anhydrideis filtered'ofl", dried in air, and recrystallized from ethyl ether toafford 2.4 g. of 17a ethynyl 17f!- acetoxyestr 5 en 3 one 3ethylenehemithioketal (B), white prisms fhich melt at 162165C.

Analysis.Calcd. for C H O 'S: C, 72.00; H, 8.05. Found: C,.71.75; H,8.25.

[M +1.2 (chl.).

C. The methanolic mother liquor from which the A isomerhas first beenseparated (part A) and from which the A isomer has later crystallized(part B) is reduced in volume to 60 ml. and stored at 0 C. for two daysto effect crystallization of 6.7 g. of a mixture of the isomerichemithioketals. This material may be subjected to the separation ofisomers detailed in parts A and B, but this separation is not necessaryfor conversion to the enol ether. The mixture may be used as is foracetylative cleavage to the enol ether (see Example VI, C.)

Following the procedure of Example V, but starting with:

17a-methyl-19-nortestosterone, 17a-ethyl-19-nortestosterone,17a-butyl-19-nortestosterone, 17a-propynyl-l9-nortestosterone,19-nortestosterone acetate, 6a-fluoro-17a-hydroxy-19-norprogesterone,Got-fluoro-17u-acetoxy-19-norprogesterone,6a-methyl-l7a-hydroxy-19-norprogesterone,Got-methyl-17u-acetoxy-19-norpr0gesterone,17a-ethynyl-19-nortestosterone acetate,6a-methy1-17u-ethynyl-19-nortestosterone acetate, and17a-(prop-1-yne-1-yl)-19-nortestosterone acetate there are preparedrespectively,

(A) 17a-methyl-5(10)-estren-17B-ol-3-0ne S-ethylenehemithioketal,

(B) 17ot-methyl-5-estren-17;8ol-3-one 3-ethylenehemithioketal,

(A) 17 a-ethyI-S 10)-estren-17 ,B-ol-3-one 3-ethylenehemithioketal,

(B) 17a-ethyl-5-estren-l7 f3-ol-3-one 3-ethylenehemithioketal,

(A) 17a-butyl-5(10)-estren-17fl-ol-3-one 3-ethylenehemithioketal,

(B) 17u-butyl-5-estren-175-01-3 -one 3-ethylenehemithioketal.

(A) 17a-propynyl-5 10) -estren-17fl-ol-3-one 3-ethylenehemithioketal,

(B) 17a-propynyl-5-estren-l7 3-ol-3-one S-ethylenehemithioketal,

(A) 5 )-estren-17fl-ol-3-one 17-acetate 3-ethylenehemithioketal,

(B) 5-estren-17B-ol-3-one l7-acetate 3-ethylenehemithioketal,

(A) 6a-fiuoro-17u-hydr0xy-19-norpregn-5 10)-ene- 3,20-dione3-ethylenehemithioketal,

(B) 6-fluoro-17a-hydroxy-19-norpregn-5-ene-3,20-dione3-ethylenehemithioketal,

(A) 6a-fluoro-17a-acetoxy-19-norpregn-5 10)-ene-3,20*-

dione 3-ethylenehemithioketal,

(B) 6-fiu0ro-17u-acetoxy-19-norpregn-5-ene-3,ZO-dione3-ethylenehemithioketal,

(A) Gu-methyl-l7a-hydroxy-19-norpregn-5 10)-ene- 3,20-dione3-ethylenehemithioketal,

(B) 6-methyl-17a-hydroxy-19-norpregn-5-ene-3,20 dione3-ethylenehemithioketal,

(A) 6a-methyl-17ot-acetoxy-19-norpregn-5(10)-ene-3,

20-dione 3-ethylenehemithioketal,

(B) 6-methyl-17a-acetoxy-l9-norpregn-5-ene-3,20-dione3-ethylenehemithioketal,

(A) 17a-ethynyl-17,8-acetoxyestr-5(10)-en-3-one 3-ethylenehemithioketal,

(B) 17a-ethynyl-17/3-acetoXyestr-5-en-3-one B-ethylenehemithioketal,

(A) 6a-methyl-17a-ethynyl-17B-acetoxyestr-5 10 -en- 3-one3-ethylenehemithioketal,

(B) 6-methyl-17u-ethynyl-17B-acetoxyestr-5-en-one3-ethyler1ehemithioketal,

(A) 17a-(prop-1-yne-1-yl) -17fi-acetoxyestr-5( 10 -en- 3-one3-ethylenehemithioketal, and

(B) 17a-(prop-1-yne-l-y1) -17,8-acet-oxyestr-5-en-3 -oneS-ethylenehemithioketal.

Example VI.-3- B-acetylthioethoxy -1 7a-ethynyl-1 75-acetoxyestra-3,5-diene A. A mixture of 1.1 g. of17a-ethynyl-17,6-acetoxyestr- 5(10)-en-3-one 3-ethylenehemithioketal (asobtained in Example V, A) and 0.6 of p-toluenesulfonic acid monohydratein 20 ml. of acetic anhydride is stirred vigorously at 25 C. for onehour, and then 5 ml. of pyridine is added and the mixture is poured into350 ml. of ice and water to which 45 ml. of pyridine has previously beenadded. The pale yellow solid which remains after hydrolysis of theacetic anhydride is filtered 01f and dried in air and then it isrecrystallized from acetone containing a few drops of pyridine to afford0.9 g. of 3-(13- acetylthioethoxy) 17a ethynyl 1713 acetoxyestra 3,5-diene, cream colored flakes which melt at 165-168 C.

Analysis.Calcd. for C H O S: C, 70.60; H, 7.74. Found: C, 70.96; H,7.90.

[(11 3 180 (chl.).

B. A mixture of 0.25 g. of 17a-ethynyl-17,8-acetoxyestr- 5-en-3-one3-ethylenehemithioketal (as obtained in Example V, B) and 0.15 g. ofp-toluenesulfonic acid monohydrate in 4 ml. of acetic anhydride isstirred vigorously at 25 C. for forty-five minutes and then the reactionmixture is Worked up as detailed in A (above) with appropriate scalingdown of quantities. Recrystallization of the crude enol ether affords0.16 g. of cream flakes which melt at 165-168 C., and whose infraredspectrum is identical with that of the material obtained in A.

C. A mixture of 4.0 g. of the mixture of A and A -hemithioketal isomers(as isolated in Example V, C) and 2.4 g. of p-toluenesulfonic acidmonohydrate in ml. of acetic anhydride is stirred vigorously at 25 C.for forty-five minutes and then the reaction mixture is Worked up asdetailed in A (above) with appropriate scaling up of quantities.Recrystallization of the crude, air-dried enol ether from acetoneafiords 2.95 g. of cream flakes which melt at 168 C., and whose infraredspectrum is identical with that of the material obtained in A.

Following the procedure of Example VI, but starting with:

(A) 17a-methyl-5 10)-estren-175-ol-3-one 3-ethylenehemithioketal,

(B) 17zx-methyl-5-estren-17,8-ol-3-o11e 3-ethylenehemithioketal,

(A) 17u-ethyl-5(10)-estren-17;8-ol-3-one 3-ethylenehemithioketal,

(B) 17a-ethyl-5-estren-17,8-ol-3-one 3-ethylenehemithioketal,

(A) 17u-butyl-5(10)-estren-17p-ol-3-one 3-ethylenehemithioketal,

(B) 17a-butyl-5-estren-17,8-01-3 -0ne 3-ethylenehemithioketal,

(A) 17a-propynyl-5(10)-estren-17fi-ol-3-one 3-ethylenehemithioketal,

(B) 17u-propyny1-5-estren-17,6-ol-3-one 3-ethylenehemithioketal,

(A) 5(10)-estren-l7fl-ol-3-one 17-acetate S-ethylenehemithioketal,

(B12 5-estren-17B-0l-3-one 17-acetate 3-ethylenehemithioetal,

(A) a-fiuoro-17a-hydroxy-19-norpregn-5(10)-ene-3,20-

dione 3-ethylenehemithioketal,

(B) 6-fluoro-17a-hydroxy-19-norpregn-5-ene-3,20-dione3-ethylenehemithioketal,

(A) 6u-fluoro-17u-acetoxy-19-norpregn-5(10)-ene-3,20-

dione 3-ethylenehernithioketal,

(B) 6-fluoro-l7a-acetoxy-19-norpregn-5-ene-3,20-dione3-ethylenehemithioketal,

(A) 6a-methyl-17a-hydroxy-19-norpregn-5 10) -ene- 3,20-dione3-ethylenehemithioketal,

(B) 6-methyl-17a-hydr0xy-l9-norpregn-5-ene-3,20-dione3-ethylenehernithioketal,

(A) 6a-methyl-17x-acetoxy-19-norpregn-5 10)-ene-3,20-

dione 3-ethylenehemithioketal,

(B) 6-methyl-17u-acetoxy-19-norpregn-5-ene-3,20-dione3-ethylenenhemithioketal,

(A) 17 a-ethynyl-17fi-acetoxyestr-5 10)-en-3-one3-ethylenehemithioketal,

(B) 17a-ethynyl-17fl-acetoxyestr-5-en-3-one 3-ethylenehemithioketal,

(A) 6a-methyl-171x-ethynyl-17/3-acetoXyestr-5 ()en-3- one3-ethylenehemithioketal,

(B) 6' methyl-17a-ethynyl-17,8-acetoXyestr-5-en-3-one3-ethylenehemithioketal,

(A) 17bt-(prop-1-yne-1-yl)-17;3-acetoXyestr-5 lO)-enone3-ethylenehemithioketal, and

(B 17a-(prop-l-yne-1-yl)-17fl-acet0Xyestr-5-en-3-one3-ethylenehemithioketal there are prepared" respectively,

In the foregoing examples, the steroidal 4-en-3-onesare reacted withfi-mercaptoethanol to form the corresponding 3-ethylene-hernithioketal.By reacting the steroidal 4-en-3-ones with 'y-mercaptopropanol, thecorresponding propylenehemithioketals are formed. Upon cleavage of thepropylenehemithioketal moiety, the corresponding y-acetylthiopropoxycompounds are obtained.

What is claimed is:

1. A compound selected from the group consisting of wherein Ris-selected from the group consisting of hydrogen, methyl, fluoro andchloro, R is selected from the group consisting of hydrogen and methyl,R" is selected from the group consisting of hydroxy, acetyl and acetoxy,R' is selected from the group consisting of hydrogen, lower alkyl offrom 1 to 8 carbon atoms, lower acyloxy of from 1 to 8 carbon atoms and-C CX wherein X is selected from the group consisting of hydrogen,chloro and lower alkyl of from 1 to 8 carbon atoms and n is thein'teger2 or 3.

2. 17a acetoxypregn 5 ene 3,20 dione 3 ethylenehe-mithioketal as claimedin claim 1.

3. 6 methyl 17a acetoxypregn- 5 ene 3,20- dione 3-ethylenehemithioketalas claimed in claim 1.

4. 171x ethynyl-1713-acetoXyestr-5(10)-en-3-one 3-ethylenehemithioketalas claimed in claim 1.

5. a ethynyl 17B acetoxyestr 5 en 3 on 3-ethylenehemithioketal asclaimed in claim 1.

wherein R is selected from the group consisting of by drogen, methyl,chloro, and fluoro, R is selected from from the group consisting ofhydrogen and methyl, R" is selected from the group consisting of acetyland acetoxy, R' is selected from the group consisting of hydrogen, loweralkyl of from 1 to 8 carbon atoms, loweracyloxy of from 1 to 8 carbonatoms and CECX wherein X is selected from the group consisting ofhydrogen, chloro and lower alkyl of from 1 to 8 carbon atoms, and n isthe integer 2 or' 3.

7. 3 (,8 acetylthioethoxy) 17cc acetoxypregna- 3,5-diene-20-one asclaimed in claim 6.

8. 3 (B acetylthioethoxy) 6 methyl 171x acetoXypregna-3,S-diene-ZO-oneas claimed in claim 6.

9. 3 (,8 acetylthioethoxy) 17a ethynyl 17,8- acetoxyestra-3,5-diene asclaimed in claim 6.

References Cited UNITED STATES PATENTS 2,288,854 7/1942 Stavely 260-239.S5 2,793,217 5/1957 Muller zen-397.45 3,162,629 12/1964 Scheer260-239.5

OTHER REFERENCES Karmas: Tetrahedron Letters No. 18, pp. 1093-4098(1964) (p. 1095 relied on).

Weiss et al.: J. Med, Chem. 7, pp. 804-806 (1964).

Zderic et al.; Chem. Abstr., 54, 1602g (1960)..

LEWIS GOTTS, Primary Examiner.

T. M. MESHBESHER, Assistant Examiner,

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,354,153 November 21, 1967 George Karmas It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 1, line 41, for "3703-8" read 3704-8 column 5, line 2, for"motor" read mother line 15, for "4-ethylenehemithioketa1s" readS-ethylenehemithioketals column 6, line 22, for "6-chloro" read6a-ch1oro column 7, line 3, for ".88" read 5.88

Signed and sealed this 18th day of February 1969.

(SEAL) Attest:

Edward M. Fletcher, Jr. Attesting Officer EDWARD J. BRENNER Commissionerof Patents

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF